tbuckley/cabot-search huggingface dataset:
IMMU-02. Targeted innovative antibody fragment-based immunotherapy for medulloblastoma
Authors: Judith Niesen, Christina Krüger, Naomé Kreuter, Undine Haferkamp, Ole Pless, Ulrich Schüller
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumor accounting for ~20 % of childhood brain tumors. One third of all MB are characterized by constitutive activation of the Sonic Hedgehog (SHH)-signaling pathway. This tumor type shows overexpression of the epidermal growth-factor receptor (EGFR), which we detected in SHH-MB patient samples, transgenic SHH MB mouse models, and MB-cell lines. In contrast, non-neoplastic cells only express EGFR at low levels. Intensive radio-/chemotherapy often leaves the young patients with significant long-term burdens including problems in brain development and cognitive deficits. Thus, there is an urgent need to develop new targeted therapies that can prevent tumor recurrence without affecting healthy cells. We selected EGFR as a potential therapy target using EGFR-specific antibody fragments (scFvs) as part of immunoconjugates, namely bispecific T-cell engagers (BiTEs) and immunotoxins (ITs). Both, the EGFR-specific BiTEs and the ITs showed specific binding and cytotoxic activity in MB cells. Effector- and target-cell specificity was demonstrated via flow cytometry for the BiTEs. BiTEs and ITs selectively killed MB-tumor cells and showed pro-apoptotic effects without unspecific effects. Furthermore, preliminary results from an innovative hiPSC-based in vitro-BBB-model suggest, that the ITs are able to cross the BBB. Finally, by having a functional cloning- and expression system for the BiTEs and ITs available, target-scFvs can be easily exchanged by novel antigens or peptides to obtain additional targeted immunotherapies. Together, these results pave the way for preclinical in vivo experiments and future clinical trials in patients with SHH MB.
The Toronto Upper Gastrointestinal Cleaning Score: a prospective validation study
Authors: Rishad Khan, Nikko Gimpaya, Jose I. Vargas, Anushka Ramkissoon, Samir Seleq, Reza Gholami, Hisham J. Akhtar, Rishi Bansal, Michael A. Scaffidi, Sunil Amin, Steven Bollipo, Jan Kral, Rashid Lui, Katarzyna M. Pawlak, Dalbir S. Sandhu, Mohammad Bilal, Enrique de-Madaria, Keith Siau, Aline Charabaty, Almoutaz Hashim, Sergio A. Sánchez-Luna, Christopher W. Teshima, Gary R. May, Jeffrey D. Mosko, Catharine M. Walsh, Samir C. Grover
Journal: Endoscopy (2022)

Background Assessment of mucosal visualization during esophagogastroduodenoscopy (EGD) can be improved with a standardized scoring system. To address this need, we created the Toronto Upper Gastrointestinal Cleaning Score (TUGCS). Methods We developed the TUGCS using Delphi methodology, whereby an international group of endoscopy experts iteratively rated their agreement with proposed TUGCS items and anchors on a 5-point Likert scale. After each Delphi round, we analyzed responses and refined the TUGCS using an 80 % agreement threshold for consensus. We used the intraclass correlation coefficient (ICC) to assess inter-rater and test–retest reliability. We assessed internal consistency with Cronbach’s alpha and item-total and inter-item correlations with Pearson’s correlation coefficient. We compared TUGCS ratings with an independent endoscopist’s global rating of mucosal visualization using Spearman’s ρ. Results We achieved consensus with 14 invited participants after three Delphi rounds. Inter-rater reliability was high at 0.79 (95 %CI 0.64–0.88). Test–retest reliability was excellent at 0.83 (95 %CI 0.77–0.87). Cronbach’s α was 0.81, item-total correlation range was 0.52–0.70, and inter-item correlation range was 0.38–0.74. There was a positive correlation between TUGCS ratings and a global rating of visualization (r = 0.41, P = 0.002). TUGCS ratings for EGDs with global ratings of excellent were significantly higher than those for EGDs with global ratings of fair (P = 0.01). Conclusion The TUGCS had strong evidence of validity in the clinical setting. The international group of assessors, broad variety of EGD indications, and minimal assessor training improves the potential for dissemination.
Estimated doses of radiation received by the eye lens during endourological procedures: Are we being careful enough? ESUT-YAU endourology group collaboration
Authors: A. Bravo-Balado, S. Fontanet, A. Skolarikos, A. Serdar Gozen, B. Somani, O. Traxer, M. Talso, L. Villa, A. Papatsoris, A. Pietropaolo, S. Tonyali, E.X. Keller, T. Tailly, P. Kallidonis, E. Sener, U. Nagele, E. Emiliani
Journal: European Urology (2022)
Prior authorizations for PARP inhibitors in ovarian cancer.
Authors: Audra Hugo, Daniella Pena, Emily Meichun Ko, Ashley Ford Haggerty, Anna Jo Bodurtha Smith
Journal: Journal of Clinical Oncology (2022)

5549 Background: PARP inhibitors improve survival in ovarian cancer, especially in patients with BRCA 1/2 mutations or homologous recombination deficiency (HRD). However, these FDA-approved drugs cost $100,000 annually on average, and concerns have been raised about insurance barriers like prior authorization to such medications. Our objective was to examine the prevalence of prior authorization for PARP inhibitors in ovarian cancer overall, by frontline or recurrent maintenance, and by genetic status. Methods: We performed a retrospective cross-sectional study of ovarian cancer patients prescribed a PARP inhibitor within the University of Pennsylvania oncology practices from May 2020-2021. Using electronic medical records, we assessed the prevalence of prior authorization for PARP inhibitors overall, by frontline or recurrent maintenance, and by BRCA or HRD status. We then assessed the associated approval and appeal rates. Results: We identified 110 patients with ovarian cancer who were prescribed a PARP inhibitor. Of these, 67% (95%CI 57-75) experienced prior authorization for their PARP inhibitor. In contrast, 31 (95%CI 23-40) experienced prior authorization for other components of their gynecologic oncology care. Of patients in the frontline setting, 74 (95%CI 58-86) experienced prior authorization for FDA-approved PARP maintenance. Of patients prescribed PARP maintenance after recurrence, 58 (95%CI 45-71) experienced prior authorization. Of patients with germline BRCA, 70% (95%CI 47-85) experienced prior authorization for PARP inhibitors. Of patients with germline or somatic BRCA or HRD+, 76% (95%CI 61-87) experienced prior authorization. 95% (95%CI 86-94) of prior authorizations for PARP inhibitors were approved on their 1 st appeal, and 99% (95%CI 95-100) were approved by the 2 nd appeal. Conclusions: Two-thirds of patients of ovarian cancer patients who were prescribed PARP inhibitor experienced prior authorization, including equally high rates among women with germline or somatic BRCA mutations, as well as with HRD-deficient tumors. Given the nearly 100% approval after prior authorization, improvements in insurance processes are needed to streamline PARP inhibitor access in ovarian cancer.
The increasing incidence of alcohol-related cancers in young adults in the United States: Who is most at risk?
Authors: Atharva Rohatgi, Cheng-I Liao, Michelle Ann Caesar, Caitlin Ruth Johnson, Joshua Elbridge Chan, Daniel Stuart Kapp, John K Chan
Journal: Journal of Clinical Oncology (2022)

10563 Background: To evaluate incidences and trends of alcohol-associated cancers in United States adults over the last 18 years. Methods: Data was extracted from the United States Cancer Statistics database from 2001 to 2018. SEER*Stat Joinpoint Regression program 4.8.1 was used to calculate incidences and trends. Average annual percentage change (AAPC) was used to describe trends. Based on the ICD-O-3 criteria, liver, colon, oral cavity, esophagus, and pharynx cancers were classified as alcohol-related cancers. Results: Over the last 18 years, the incidence of alcohol-associated cancers decreased overall in males and females by 0.9% every year (p &lt; 0.001). Alcohol-associated cancers increased significantly in younger patients under the age of 39 years old (p &lt; 0.001). Based on race, Black men and women had the highest incidence at 135.17/100,000 followed by 132.50 in White individuals, 105.84 in Hispanic individuals, and 104.28 in Asian individuals. By region, the incidence was found to be the highest in the Midwest at 132.89/100,000 and lowest in the West at 120.33. Based on cancer types, the most common alcohol related cancer was colorectal cancer with an incidence at 36.49/100,000 in 2018, followed by oral cavity cancers at 11.69, liver cancer at 6.76, esophagus cancer at 4.51, and larynx cancer at 2.92. Of all these types of cancers, liver cancer had the highest annual increase at 2.43% (p &lt; 0.001). Using a projection model, we found that liver cancer is estimated to surpass colorectal cancer by the year 2035. On intersectionality analysis, White men and women in the Northeast between the ages of 75-79 had the highest incidence of alcohol-associated cancers at 584.10/100,000 in 2018. However, over the last 18 years, White men and women in the South between the ages of 20-24 had the highest annual increase at 4.08% (p &lt; 0.001). Conclusions: Over the last 18 years, alcohol-related cancers increased in the younger patients, particularly those residing in the South. Liver cancer is increasing at the highest rate.
BCL10 mutations define distinct dependencies guiding precision therapy for DLBCL
Authors: Min Xia, Liron David, Matt Teater, Johana Gutierrez, Xiang Wang, Cem Meydan, Andrew Lytle, Graham W. Slack, David W. Scott, Ryan D. Morin, Ozlem Onder, Kojo S.J. Elenitoba-Johnson, Nahuel Zamponi, Leandro Cerchietti, Tianbao Lu, Ulrike Philippar, Lorena Fontan, Hao Wu, Ari M. Melnick
Journal: Cancer Discovery (2022)

Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825.
Development of a novel diagnostic model for urological cancers using comprehensive N-glycan signatures of serum immunoglobulins with a machine learning approach
Authors: H. Iwamura, T. Yoneyama, H. Kodama, K. Ozaki, Y. Ozaki, K. Okita, S. Konishi, T. Narita, N. Fujita, Y. Kojima, T. Okamoto, Y. Tobisawa, H. Yamamoto, S. Hatakeyama, T. Yoneyama, Y. Hashimoto, C. Ohyama
Journal: European Urology (2022)
Racial, ethnic, and socioeconomic survival disparities among children with high-risk neuroblastoma treated on upfront Children’s Oncology Group clinical trials.
Authors: Puja J Umaretiya, Arlene Naranjo, Fan Zhang, Julie R. Park, Brian D. Weiss, Meaghan Granger, Steven G. DuBois, Rochelle Bagatell, Kira Bona
Journal: Journal of Clinical Oncology (2022)

10005 Background: Racial and socioeconomic disparities have not been comprehensively investigated in high-risk neuroblastoma (HR NBL). Prior Children’s Oncology Group (COG) investigations have demonstrated population-based disparities in late relapse rates among Black children, and trial-based disparities in relapse and survival among children living in poverty receiving post-consolidation immunotherapy. It is unknown whether these disparities persist in upfront trials for newly diagnosed patients. We leveraged COG data to investigate race, ethnicity, and socioeconomic disparities in a cohort of children with HR NBL treated on upfront clinical trials from 2007-2016. Methods: Retrospective cohort study of children enrolled on upfront COG HR NBL trials ANBL0532, ANBL09P1, and ANBL12P1. Race and ethnicity were the primary exposures categorized as: Black Non-Hispanic (BNH); Hispanic; Other Non-Hispanic (ONH); or White Non-Hispanic (WNH). Poverty was the secondary exposure, defined as household (public insurance only vs others), area (census-defined high-poverty ZIP code with &gt;20% of population living below 100% Federal Poverty Level (FPL) vs &lt;20% below 100% FPL), and rural (Census-defined rurality measures linked to ZIP code). Overall (OS) and event-free (EFS) survival from time of trial enrollment were plotted by Kaplan-Meier methods; associations with race/ethnicity and poverty were evaluated by log-rank tests. Results: Among 696 children, 16% were BNH, 11% Hispanic, 4% ONH, and 69% WNH. One-third (33%) of children were household poverty-exposed, 26% area poverty-exposed, and 15% rural-exposed. Tumor stage and biology did not differ by race/ethnicity or poverty measures. Five-year OS differed significantly by race/ethnicity (47% Hispanic vs. 50% ONH vs. 61% WNH vs. 62% BNH; p=0.047). Five-year OS was inferior among children exposed to household-poverty (53% vs. 63%; p=0.036) and neighborhood-poverty (54% vs. 62%; p=0.050) compared to unexposed children. There was no difference in OS by rurality. Similar directionality in 5-year EFS outcomes by race/ethnicity and poverty were observed without statistical significance. Conclusions: Race/ethnicity and poverty-exposure are associated with inferior OS outcomes among children with HR NBL despite uniform planned treatment on upfront COG trials. Investigation of mechanisms driving these disparities, including disparate early phase trial enrollment are ongoing to inform targeted health equity interventions to improve outcomes.
Retrospective analysis of responses to second-line treatments of multiple myeloma after disease progression in patients who underwent ASCT.
Authors: Hussein Awada, Adel Hajj Ali, Muhammad Faizan Ali, Shubham Adroja, Gauranga Mahalwar, Ashish Kumar, Arslan Babar, Faiz Anwer
Journal: Journal of Clinical Oncology (2022)

e20004 Background: Most Multiple Myeloma (MM) patients who respond to initial treatment ultimately progress. Data regarding 2 nd line treatment remains scarce, but in general treatment relies on whether the disease is refractory to Lenalidomide (R) or not. Here, we report responses to 2 nd line treatments of MM patients in with disease progression (PD) following Autologous Stem Cell Transplant (ASCT). Methods: We retrospectively reviewed MM patients with PD after ASCT at Cleveland Clinic during the period of April 1, 2016 till December 31, 2021. Baseline demographic, clinical and cytogenetic features were obtained from electronic records. Patients who had PD after ASCT, as defined by IMWG criteria, were divided into two smaller subcohorts: R-refractory and R-sensitive. Outcomes were compared among treatment groups within each subcohort. Continuous variables are reported as means with standard deviations, while categorical variables are presented as percentages. Categorical variables were compared using the chi-squared test while the t test and ANOVA were used for continuous variables. Results: 127 patients who had PD following ASCT were identified (Table). Most common cytogenetic aberrancies were del(13) (RB) 34.6%, t(11;14) 18.9% and gain(1q) 15%. Pre-PD maintenance included R 58.3%, Bortezomib (V) 7.1%, RV combination 8.7% and other R-based regimens 9.4%, with no difference in time to disease progression (TTPD) between them (p = 0.82), and an average of 15.5 months TTPD among all patients. ISS III patients were likely to progress earlier than ISS II or I (10.91 vs 14.56 vs 20.33 months; p = 0.008), while high and standard-risk cytogenetics did not predict TTPD (12.62 vs 16.85 months; p = 0.092). Patient who achieved CR either pre or post-ASCT were less likely to progress compared to others with weaker responses (p = 0.032; p = 0.002). Patients who did not achieve CR post-ASCT progressed earlier than those with CR (12.37 vs 16.53 months; p = 0.041). In R-sensitive patients (n = 25), PD was not significantly different in patients on 2 nd line Daratumumab (D), R and dexamethasone (d) vs RVd (45.5% vs 60%; p = 0.505). In R-refractory patients (n = 57), PD was also not significantly different in DVd, Dd with Pomalidomide, or Carfilzomib (C)-based regimens (81.3% vs 68.2% vs 60%; p = 0.426). Time to 2 nd PD was significantly longer in DRd vs RVd (12.4 vs 3 months; p = 0.026) but similar in DVd vs DPd vs C-based regimens (6.75 vs 8 vs 5.89 months; p = 0.711). Conclusions: TTPD in MM post-ASCT is determined by the ISS stage and achieving CR but not by cytogenetic risk or maintenance choice. Current regimens used as 2 nd line in R-refractory patients are statistically indifferent, but DRd delays further PD compared to RVd in R-sensitive patients.[Table: see text]
OTHR-20. Precision neuro-oncology in the real world. Opportunity and challenges from a UK Oncology Centre
Authors: John Apps, Andrew Peet, Martin English, Jenny Adamski
Journal: Neuro-Oncology (2022)

Abstract The last five years has shown advances in the molecular classification of brain tumour, molecular profiling techniques and an increased use of targeted therapies. We reviewed the molecular analysis pathways and use of targeted agents at Birmingham Children’s Hospital (BCH), a large (~55 new cases/year) neuro-oncology centre, between 2016-2021. Having previously been analysed locally by limited directed immuno-histochemical stains and referral for specific genetic tests, tissue is now referred for a range of second histopathological opinions and in depth molecular classification, via methylation array, panel sequencing, RNA fusion analysis, and whole genome sequencing. These are accessed through different evolving pathways and consent processes, including referral to other centres, national reference laboratories, clinical studies, and local genetics laboratories with links to national sequencing infrastructures. Different routes result in different reporting structures, timescales and with varying levels of interpretation, often without adequate access to clinical information and context. 21 patients were treated on five targeted agent clinical trials (Afatanib (n=6), Biomede (n=3), eSmart(n=1), PARC (n=7), Vinilo (n=5)), with one patient on both Afatanib and PARC trials. A further two patients visited other centres for trials. Eight patients received MAPK pathway inhibitors through compassionate access pathways, with benefit, including radiological response, in four. Cardiac toxicity was observed in three and retinal oedema in one. Two patients received immune checkpoint inhibition, with rapid fatal enlargement, either progression or pseudo-progression, in one case. These rapid changes in diagnostic and management options offer new opportunities for patients, but bring challenges to the delivery of neuro-oncology services, including the logistics of sample, report, clinical trial, compassionate access management and the increased multi-specialist support required for monitoring and management of toxicities. Integration of targeted agents into the appropriate part of a patient’s treatment strategy requires skilled interpretation of the benefits compared to conventional therapies.
Effectiveness of pyronaridine-artesunate against Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections: a post-hoc analysis of the CANTAM-Pyramax trial
Authors: Mirjam Groger, Gaston Tona Lutete, Ghyslain Mombo-Ngoma, Nsengi Y Ntamabyaliro, Gauthier Kahunu Mesia, Trésor Bodjick Muena Mujobu, Lia Betty Dimessa Mbadinga, Rella Zoleko Manego, Diane Egger-Adam, Isabelle Borghini-Fuhrer, Jangsik Shin, Robert Miller, Sarah Arbe-Barnes, Stephan Duparc, Michael Ramharter
Journal: The Lancet Microbe (2022)

BackgroundHigh-quality evidence for the therapeutic efficacy and effectiveness of antimalarials for infections caused by Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections is scarce. In this study, we aimed to analyse the efficacy of pyronaridine–artesunate for the treatment of non-falciparum and mixed-species Plasmodium infections from a large phase 3b/4 clinical trial in central Africa.MethodsThis post-hoc analysis was done in a random subset of samples from two sites (in the Democratic Republic of the Congo and in Gabon) of the CANTAM-Pyramax trial assessing pyronaridine-artesunate therapy. We randomly selected paired dried blood spot samples from day 0 and day 28 (or unforeseen visit) and analysed them by quantitative PCR for mixed Plasmodium infections or non-falciparum mono-infections. Day 28 (or unforeseen visit) samples positive for non-falciparum malaria were re-assessed by microscopy to identify microscopic versus submicroscopic infections. Analyses were done on two sample sets: a per-protocol set and an intention-to-treat set.FindingsAmong 1502 randomly selected samples, 192 (12·8%) showed mixed-Plasmodium infections or non-falciparum mono-infections. We did not detect P vivax in the samples. For both the per-protocol and intention-to-treat sets, the overall day 28 cure rates for P malariae, P ovale curtisi, and P ovale wallikeri were 96·3% or higher (95% CIs from 81·0–99·9 to 95·7–100). Cure rates were consistently high in P malariae (99·2%, 95·7–100) and P ovale spp (97·9%, 88·7–99·9, for P ovale curtisi and 96·3%, 81·0–99·9, for P ovale wallikeri) infections.InterpretationThis post-hoc analysis provides important evidence supporting the high efficacy of pyronaridine-artesunate against mono-infections with P malariae, P ovale curtisi, or P ovale wallikeri and mixed-Plasmodium infections in a real-world setting.FundingMedicines for Malaria Venture.